1. Field of the Invention
The invention relates to a process for preparing enantiomer-enriched 3-heteroaryl-3-hydroxypropanoic acid derivatives and 3-heteroaryl-1-aminopropan-3-ols, and to their use.
2. Brief Description of the Prior Art
3-Heteroaryl-3-hydroxypropanoic acid derivatives and 3-heteroaryl-1-aminopropan-3-ols have gained industrial significance, in particular, as intermediates for producing medicaments. Illustratively, some 3-heteroaryl-3-hydroxypropanoic acid derivatives and 3-heteroaryl-1-aminopropan-3-ols are used as precursor substances for preparing inhibitors of the uptake of serotonin or noradrenaline. In the case of some of these inhibitors, it has been shown that certain enantiomers are not only inactive, or less active, but are even able to exhibit undesirable side-effects (U.S. Pat. No. 5,104,899).
The art-known processes for preparing these enantiomers and the attendant disadvantages are as follows. A process for preparing enantiomer-enriched (1S)-3-(methylamino)-1-(2-thiophenyl)-1-propanol proceeding from 1-(2-thiophenyl)-3-chloropropan-1-one is described in Chirality 2000, 12, 26-29. Following reduction to the racemic 3-chloro-1-(2-thienyl)-1-propanol, the racemate is resolved enzymically and the (S) enantiomer is subjected to further reaction with Nal and methylamine to give (S)-3-(methylamino)-1-(2-thiophenyl)propan-1-ol. This method suffers from the disadvantage that, in principle, only 50% of the desired enantiomer can be obtained when racemates are resolved enzymically and the total yield is therefore economically unacceptable.
It is known that microorganisms, such as yeasts or fungi, can be used to reduce 3-oxocarboxylic acid derivatives enantioselectively to give the corresponding enantiomer-enriched 3-hydroxycarboxylic acid derivatives (see also Sybesma et al., Biocatalysis and Biotransformation, 1998, Vol. 16, 95-134; Dahl et al., Tetrahedron: Asymmetry 10, 1999, 551-559, Dehli et al., Tetrahedron: Asymmetry 11, 2000, 3693-3700, Hayakawa et al, Tetrahedron Letters, 1998, Vol. 39, 67-70, Cabon et al., Tetrahedron: Asymmetry 6, 1995, 2199-2210 and Smallridge et al., Tetrahedron Letters, 1998, Vol. 39, 5121-5124).
In addition, EP-A 447 938 describes the enantioselective synthesis of 2-halo-3-hydroxy-3-phenylpropanoic esters by using various organisms to reduce the 2-halo-3-oxo-3-phenylpropanoic esters.
Furthermore, Chenevert et al., Tetrahedron 1992, Vol.48, 6769-6776 disclose the asymmetric synthesis of both enantiomers of the antidepressant fluoxetine (N-methyl-3-(4-trifluoromethylphenoxy)-3-phenylpropylamine hydrochloride). An important step in the multi-stage synthesis is that of using microorganisms to effect the enantioselective reduction of the ethyl 3-oxo-3-phenylpropanoate.
An analogous synthesis, for preparing (R)-tomoxetine, which acts as an antidepressant, is described in Kumar A. et al., Tetrahedron Letters, 1991, Vol. 32, 1901-1904. Reportedly, the enantioselective reduction of the ethyl 3-oxo-3-phenylpropanoate to give ethyl 3-hydroxy-3-phenylpropanoate is an important step in this synthesis as well.
However, the enantioselective reduction of heteroaryl ketones has not previously been described.
There was still the need to provide a process which makes it possible to prepare enantiomer-enriched 3-heteroaryl-3-hydroxypropanoic acid derivatives.